The sense of taste is important for determining food choice, for regulating food intake, and for ensuring efficient use of ingested nutrients. Taste can act as a warning system for the presence of potentially harmful foods, by, for example, the aversive sensations of sourness or bitterness, and as an attractant to potentially nutrient-rich foods, by, for example, the appealing sensations of sweetness, saltiness, and umami.
Taste stimuli are received by taste receptor cells assembled into taste buds that are located in the epithelium of taste papillae of the tongue (Kitagawa et al., Bioch. Bioph. Res. Comm., 283:236-242 (2001)). The stimuli are believed to be transduced by taste receptors at the surface of the taste receptor cells (Id.). The taste receptors encoded by the genes of a given species are reflective of that species' food choices. For example, the “sweet receptors” of an herbivorous species are expected to be different from those of a carnivorous species, since the two consume completely different diets whose foods contain different primary stimuli. Since taste receptor specificity likely reflects food choice, it follows that receptor sequence homology among species may be as predictive or more predictive of food preferences of a given species as phylogenetic relatedness among species.
The behavior of the domestic cat (Felis catus), a carnivore, towards stimuli such as sweet carbohydrates, which it generally cannot taste, and towards L-amino acids, which it generally can taste, should be explicable by the specificity of taste receptors of other carnivores. Direct knowledge of taste receptor genes will allow insight into an animal's sensory world and may be useful for identifying modulators of the taste receptors encoded thereby to influence an animal's taste preferences.
Molecular receptors for the taste element of sweetness have been identified from human, mouse, and rat. Thus far, there are three known members of the T1R taste receptor family: T1R1, T1R2, and T1R3 (Montmayeur & Matsunami, Curr. Opin. NeurobioL, 12(4):366-371 (2002)). The T1R3 receptor gene is located within the Sac locus, the primary genetic locus controlling preference for sweet-tasting stimuli in mice (Li et al., Mamm. Genome, 12(1):13-16 (2001); Li et al., Mamm. Genome, 13(1):5-19 (2002)). The human syntenic region for mouse T1R3 gene is on 1p36.33 (1162-1186 kb). The gene for T1R1 is located on human 1p36.23 (6324-6349 kb), which is ˜5 Mb from T1R3, and that for T1R2 is located on human 1p36.13 (18483-18729 kb), which is ˜12 Mb from T1R1.
Most of the T1Rs are G-protein coupled receptors with long N-terminal extracellular domains believed to be involved in ligand binding (Montmayeur & Matsunami, Curr. Opin. Neurobiol., 12(4):366-371 (2002)). The T1R receptors have been shown to dimerize. For example, homodimerization of T1Rs has been detected (Zhao et al., Cell, 115:255-266 (2003)). The taste receptors also heterodimerize. For example, coupling of T1R3 with T1R1 or T1R2 has been detected. In mouse, the T1R1/T1R3 heterodimer functions as a receptor for selected amino acids. The T1R2/T1R3 heterodimer functions as a receptor for stimuli considered sweet by humans. Current data indicate that the T1R3 component of the T1R dimer couples the taste receptor to cellular signal transduction processes, thereby ensuring that the stimulus-binding event is transduced to a neural signal. Thus, knowledge of the T1R receptors will lead to better understanding of species-specific reactions to sapid stimuli.
Currently, mechanisms for identifying novel taste stimuli for the domestic cat are limited, for example, to exhaustive and difficult feeding studies in which a novel ingredient is paired with a control ingredient and intake of the two are compared. Considerable time, effort, and expense can be expended in the discovery of a single stimulus. Furthermore, feline illnesses often are exacerbated by a cat's refusal to eat. Additionally, the molecular features that define acceptable taste stimuli for domestic cat remain largely unknown, making rational computational design approaches for taste stimuli difficult. As a result, knowledge of the feline taste receptor and its ligands may lead to a better understanding of cat taste perception and modulation thereof.
The present invention provides novel genes encoding the feline taste receptors T1R1, T1R2, and T1R3, the polypeptides encoded thereby, and methods of use of the receptors to identify compounds that can stimulate, inhibit, or modify the ingestive responses or general behavior of a cat. The screening methods of the invention allow the rapid screening of binding partners, agonists, antagonists, and modulators of the T1R receptors of the domestic cat. The results of the feline T1R receptor studies reflect the unique taste profile of the domestic cat.